Pharmacokinetics and Metabolism of Broad-Spectrum Antivirals Remdesivir and Obeldesivir with a Consideration to Metabolite GS-441524: Same, Similar, or Different?
RNA viruses with pandemic potential pose a significant global health risk. The adenosine nucleoside analog GS-441524 is metabolized to its active GS-443902 triphosphate metabolite to inhibit a broad spectrum of RNA viruses. Intravenous (IV) remdesivir (RDV) and oral obeldesivir (ODV) are phosphorami...
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2025-06-01
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| Online Access: | https://www.mdpi.com/1999-4915/17/6/836 |
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| author | Darius Babusis Cynthia Kim Jesse Yang Xiaofeng Zhao Guoju Geng Carmen Ip Nathan Kozon Hoa Le Jennifer Leung Jared Pitts Dustin S. Siegel Rao Kalla Bernard Murray John P. Bilello Roy Bannister Richard L. Mackman Raju Subramanian |
| author_facet | Darius Babusis Cynthia Kim Jesse Yang Xiaofeng Zhao Guoju Geng Carmen Ip Nathan Kozon Hoa Le Jennifer Leung Jared Pitts Dustin S. Siegel Rao Kalla Bernard Murray John P. Bilello Roy Bannister Richard L. Mackman Raju Subramanian |
| author_sort | Darius Babusis |
| collection | DOAJ |
| description | RNA viruses with pandemic potential pose a significant global health risk. The adenosine nucleoside analog GS-441524 is metabolized to its active GS-443902 triphosphate metabolite to inhibit a broad spectrum of RNA viruses. Intravenous (IV) remdesivir (RDV) and oral obeldesivir (ODV) are phosphoramidate and isobutyryl-ester prodrugs of GS-441524, respectively. Following administration, both RDV and ODV show rapid and broad tissue distribution, form the same GS-443902 metabolite in target tissues, and demonstrate promising in vivo efficacy across several RNA virus infection models. In an African green monkey SARS-CoV-2 infection model, respective RDV and ODV treatments yielded similar antiviral efficacy. Here, we compare the in vitro and in vivo pharmacokinetics (PK) and metabolism of RDV and ODV to highlight both similarities and differences in their absorption, metabolism, distribution, and excretion profiles. The distinct route of administration and metabolic fate of each prodrug produced in vivo PK and metabolism profiles with differential GS-441524 to tissue GS-443902 relationships, thereby supporting alternate methods for predicting human efficacious doses. Overall, a metabolism-directed prodrug design enabled optimized delivery of the identical active GS-443902 metabolite through different routes of administration, supporting broader applications of the same nucleoside analog across an expanded spectrum of potential antiviral indications. |
| format | Article |
| id | doaj-art-d00c9813455e410caad52ea2545fcb31 |
| institution | Kabale University |
| issn | 1999-4915 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj-art-d00c9813455e410caad52ea2545fcb312025-08-20T03:29:52ZengMDPI AGViruses1999-49152025-06-0117683610.3390/v17060836Pharmacokinetics and Metabolism of Broad-Spectrum Antivirals Remdesivir and Obeldesivir with a Consideration to Metabolite GS-441524: Same, Similar, or Different?Darius Babusis0Cynthia Kim1Jesse Yang2Xiaofeng Zhao3Guoju Geng4Carmen Ip5Nathan Kozon6Hoa Le7Jennifer Leung8Jared Pitts9Dustin S. Siegel10Rao Kalla11Bernard Murray12John P. Bilello13Roy Bannister14Richard L. Mackman15Raju Subramanian16Gilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USAGilead Sciences, Inc., Foster City, CA 94404, USARNA viruses with pandemic potential pose a significant global health risk. The adenosine nucleoside analog GS-441524 is metabolized to its active GS-443902 triphosphate metabolite to inhibit a broad spectrum of RNA viruses. Intravenous (IV) remdesivir (RDV) and oral obeldesivir (ODV) are phosphoramidate and isobutyryl-ester prodrugs of GS-441524, respectively. Following administration, both RDV and ODV show rapid and broad tissue distribution, form the same GS-443902 metabolite in target tissues, and demonstrate promising in vivo efficacy across several RNA virus infection models. In an African green monkey SARS-CoV-2 infection model, respective RDV and ODV treatments yielded similar antiviral efficacy. Here, we compare the in vitro and in vivo pharmacokinetics (PK) and metabolism of RDV and ODV to highlight both similarities and differences in their absorption, metabolism, distribution, and excretion profiles. The distinct route of administration and metabolic fate of each prodrug produced in vivo PK and metabolism profiles with differential GS-441524 to tissue GS-443902 relationships, thereby supporting alternate methods for predicting human efficacious doses. Overall, a metabolism-directed prodrug design enabled optimized delivery of the identical active GS-443902 metabolite through different routes of administration, supporting broader applications of the same nucleoside analog across an expanded spectrum of potential antiviral indications.https://www.mdpi.com/1999-4915/17/6/836pharmacokineticsremdesivirobeldesivirantiviralsGS-441524GS-443902 |
| spellingShingle | Darius Babusis Cynthia Kim Jesse Yang Xiaofeng Zhao Guoju Geng Carmen Ip Nathan Kozon Hoa Le Jennifer Leung Jared Pitts Dustin S. Siegel Rao Kalla Bernard Murray John P. Bilello Roy Bannister Richard L. Mackman Raju Subramanian Pharmacokinetics and Metabolism of Broad-Spectrum Antivirals Remdesivir and Obeldesivir with a Consideration to Metabolite GS-441524: Same, Similar, or Different? Viruses pharmacokinetics remdesivir obeldesivir antivirals GS-441524 GS-443902 |
| title | Pharmacokinetics and Metabolism of Broad-Spectrum Antivirals Remdesivir and Obeldesivir with a Consideration to Metabolite GS-441524: Same, Similar, or Different? |
| title_full | Pharmacokinetics and Metabolism of Broad-Spectrum Antivirals Remdesivir and Obeldesivir with a Consideration to Metabolite GS-441524: Same, Similar, or Different? |
| title_fullStr | Pharmacokinetics and Metabolism of Broad-Spectrum Antivirals Remdesivir and Obeldesivir with a Consideration to Metabolite GS-441524: Same, Similar, or Different? |
| title_full_unstemmed | Pharmacokinetics and Metabolism of Broad-Spectrum Antivirals Remdesivir and Obeldesivir with a Consideration to Metabolite GS-441524: Same, Similar, or Different? |
| title_short | Pharmacokinetics and Metabolism of Broad-Spectrum Antivirals Remdesivir and Obeldesivir with a Consideration to Metabolite GS-441524: Same, Similar, or Different? |
| title_sort | pharmacokinetics and metabolism of broad spectrum antivirals remdesivir and obeldesivir with a consideration to metabolite gs 441524 same similar or different |
| topic | pharmacokinetics remdesivir obeldesivir antivirals GS-441524 GS-443902 |
| url | https://www.mdpi.com/1999-4915/17/6/836 |
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